Project Summary PQ #9 ?What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy- induced severe adverse sequelae? This application will focus on cardiovascular toxicity in relationship to breast cancer treatment. Targeted therapies for triple negative breast cancer (TNBC) are currently limited to standard chemotherapies such as doxorubicin (DOX), which induce cardiotoxicity. The iron chelator, dexrazoxane (DXZ), is currently the only FDA-approved drug for the prevention of DOX-induced cardiotoxicity. However, DXZ is rarely used due to multiple side effects and concerns of its ability to reduce the efficacy of DOX. Clearly there is a need for more effective treatments. We focused on the Ser/Thr protein kinase, RSK, as it is activated in failing human hearts. We found that DOX activates RSK. Importantly, inhibition of RSK using a novel RSK-specific inhibitor, which we developed, prevented DOX-induced toxicity in rat neonatal cardiomyocytes. Treatment with our RSK-inhibitor prevented the increase in DOX-induced reactive oxygen species, which is associated with DOX toxicity. Furthermore, our novel RSK inhibitor reduced TNBC metastatic colonization in vivo. We hypothesize that inhibition of RSK will potentiate the DOX-mediated inhibition of metastasis while ameliorating DOX-induced cardiotoxicity. We propose to optimize the synthetic route of our novel RSK-specific inhibitor (aim 1) and evaluate in vivo the ability of our RSK inhibitor in the presence of DOX to reduce metastasis while simultaneously functioning to prevent DOX-induced cardiotoxicity (aim 2). Based on information obtained in our proteomic analysis we will investigate the mechanism by which RSK inhibition rescues cardiomyocyte viability in the presence of DOX (aim 3). Data generated in the proposal will be analyzed using the appropriate statistics for end point and longitudinal analysis. The successful development of a RSK inhibitor could dramatically improve outcomes for those patients treated with anthracycline-based therapies.